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Process for preparing pyrimidine compound

a technology of pyrimidine and compound, applied in the field of compound, can solve the problems of inability to be said to be always industrially suitable, and conventional methods of preparing compounds used as enzyme inhibitor intermediates, etc., to achieve safe preparation, low cost, and good yield

Inactive Publication Date: 2005-07-28
AJINOMOTO CO INC
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  • Claims
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AI Technical Summary

Benefits of technology

[0008] It is another object of the present invention to provide novel intermediates which are useful for preparing enzyme inhibitors which can be prepared safely with a small number of steps at a relatively low cost and a method of preparing the same.
[0013] (2) that this intermediate can be prepared safely with a small number of steps at a relatively low cost.
[0014] Moreover, the acyl group (particularly the benzoyl group) and the like which are present in the pyrimidine compound represented by formula (1) below are difficult to remove, i.e., deprotect. In particular, in case of deprotection by a conventional method (in the presence of a strongly acidic or strongly basic compound), it had been difficult to obtain a deprotected derivative with a good yield due to the accompanying decomposition of the pyrimidine compound itself and side reactions. Thus, the present inventors conducted an extensive investigation of deprotection conditions, and, as a result, surprisingly succeeded in suppressing the decomposition and side reactions which had been problematic, by conducting the deprotection reaction in an alcohol in the presence of an alkali metal hydroxide. Accordingly, the present inventors have additionally found that by obtaining a deprotected derivative (that is, an acetic acid compound represented by formula (6) below) as a direct salt, the deprotected derivative can easily be separated and purified from the compound prepared in the deprotection reaction (corresponding to benzoic acid when the amino-protecting group is a benzoyl group.
[0015] Furthermore, the present inventors have also found that by utilizing the above-described method of preparing a pyrimidine compound and an acetic acid compound, an N-protected compound represented by formula (7) below, wherein the amino group of the acetic acid compound is protected, can be prepared safely at a relatively low cost with a good yield.

Problems solved by technology

However, because this method involves a large number of steps and uses an expensive reagent, and also because a risk of explosion associated with the Crutius rearrangement is of concern when the method is conducted on an industrial scale, the method cannot be said to be an always industrially suitable method.
Although this method is preferable in that the number of steps is smaller than that of the foregoing WO93 / 21210 and WO93 / 21214, it cannot be said to be an always industrially suitable method, because the nitroacetic acid ester is difficult to obtain industrially, and also because the risk of explosion is of concern because of its identity as a nitro compound.
As described above, there are problems in the conventional methods of preparing compounds used as enzyme inhibitor intermediates.

Method used

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  • Process for preparing pyrimidine compound
  • Process for preparing pyrimidine compound
  • Process for preparing pyrimidine compound

Examples

Experimental program
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Effect test

example 1

[0144] Hippuric acid (5.0 g, 27.9 mmol), triethyl ortho-formate (5.4 g, 36.3 mmol), and acetic anhydride (8.6 g, 83.7 mmol) were stirred, and refluxed for 3 hours. Subsequently, the mixture was cooled, toluene (50 ml) and ethanol (4 ml) were added, and the mixture was concentrated. Further, toluene (30 ml) was added and the mixture was concentrated under reduced pressure, after which hexane (10 ml) was added, and the residue was crystallized under ice cooling. The precipitate was filtered and washed with hexane, and the mother liquor was concentrated, after which hexane (2 ml) was added, and the residue was crystallized in the same manner to yield a second batch of crystals. The obtained crystals were combined and dried under reduced pressure to yield a 4-ethoxymethylene-2-phenyl-5-azlactone crystal (4.24 g, 19.5 mmol).

[0145]1H-NMR(CDCl3)δppm: 1.48-1.51 (3H,t,J=7.1 Hz), 4.42-4.47(2H,q,J=7.1 Hz), 7.35(1H, s), 7.45-7.56(3H,m), 8.06-8.09(2H,m).

example 2

[0146] N-(tert-butoxycarbonylmethyl)phenylamidine hydrochloride (4.2 g, 15.6 mmol) was stirred in toluene (6 ml), and water (6 ml), and sodium carbonate (7 g) was added. After the organic layer was separated, the water layer was extracted by the addition of toluene (5 ml), and the organic layers were combined, washed with saline, and dried with sodium sulfate. To the solution, a solution of 4-ethoxymethylene-2-phenyl-5-azlactone (2.60 g, 12.0 mmol) in acetonitrile (4 ml) was added drop by drop over 30 minutes, and this mixed solution was stirred at room temperature for 1 hour and at 80° C. overnight. Subsequently, the mixed solution was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saline, the organic layer was concentrated, hexane (12 ml) was added, and the residue was crystallized. After stirring at room temperature, the crystals were collected by filtration and dried to yield 1-(tert-butoxycarbonylmethyl)-6-oxo-2-phenyl-5-benzoylamino-1,6-dih...

example 3

[0149] To acetylglycine (0.2 g, 1.7 mmol), triethyl ortho-formate (0.76 g), acetic anhydride (1.74 g), and ethyl acetate (1.5 ml) were added, and the mixture was stirred at 95° C. overnight, after which the reaction solution was washed with saline, and the organic layer was concentrated, after which toluene (3 ml) was added, and the mixture was concentrated to dryness. N-(tert-butoxycarbonylmethyl)phenylamidine hydrochloride (2.22 mmol) was stirred in toluene (6 ml) and water, and sodium carbonate (1.6 g) was added. After the organic layer was separated, the water layer was extracted by the addition of toluene (3 ml), and the organic layers were combined, washed with saline, and dried with sodium sulfate. To the obtained solution, the previously obtained dry solid was added, and the mixture was stirred at 60° C. overnight and 80° C. overnight. The reaction solution was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, and the organi...

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Abstract

Azlactone Compound (2) is reacted with Amidine Compound (3) to give Pyrimidine Compound (1) which is useful as an intermediate for the production of enzyme inhibitors (e.g., elastase inhibitor, chymase inhibitor etc.): wherein each symbol is as defined in the specification.

Description

CROSS REFERENCES TO RELATED APPLICATIONS [0001] This application is a continuation of International Patent Application No. PCT / JP03 / 07399, filed on Jun. 11, 2003, and claims priority to Japanese Patent Application No. 2002-174916, filed on Jun. 14, 2002, both of which are incorporated herein by reference in their entireties.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to compounds which are useful as intermediates for the production of pharmaceuticals such as enzyme inhibitors (e.g., elastase inhibitor and chymase inhibitor), and a method of preparing the same. [0004] 2. Discussion of the Background [0005] Various methods of preparing enzyme inhibitors having a 5-amino-6-oxo-2-phenylpyrimidine backbone, such as elastase inhibitors and chymase inhibitor, have been reported. For example, WO93 / 21210 and WO93 / 21214 disclose a method of preparing 2-(5-(benzyloxycarbonyl)amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid, which ...

Claims

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Application Information

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IPC IPC(8): C07D239/12C07D239/46C07D263/42
CPCC07D239/47C07D239/12C07D263/42
Inventor TAKAHASHI, DAISUKEHONDA, YUTAKAIZAWA, KUNISUKE
Owner AJINOMOTO CO INC
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